Download Lipid Metabolism Catabolism Overview

3/29/2017
Lipid Metabolism
Pratt & Cornely, Chapter 17
Catabolism Overview
• Lipids as a fuel source from diet
• Beta oxidation – Mechanism
– ATP production
• Ketone bodies as fuel
1
3/29/2017
TAG and FA
• High energy
– More reduced
– Little water content
– 9 Cal/g vs 4 Cal/g for carbs
• Unsaturated FA
• Glycerol
Digestion
• Cross from intestine into bloodstream
2
3/29/2017
Lipoprotein Metabolism
• Liver is the packaging center
• VLDL are sent out of liver
• Constant cycling of LDL in blood
• Genetic cholesterol problem: no LDL receptors in non‐liver cells
• HDLs are “good cholesterol”
3
3/29/2017
Role of LDL and HDL
Utilization Stage 1:
Mobilization
Hormone Sensitive Lipase
4
3/29/2017
Utilization Stage 2:
Activation and Transport into Matrix
• FA must be attached to CoA
• High energy bond
• Costs ATP AMP (2 ATP equivalents)
5
3/29/2017
Utilization Stage 2:
Transport into Matrix
• Matrix is site of fatty acid breakdown
– Goes into citric acid cycle
• Carnitine ester: another high energy bond
• Transporter: Major site of regulation of FA degradation
Problem 7
• A deficiency of carnitine results in muscle cramps, which are exacerbated by fasting or exercise. Give a biochemical explanation for the muscle cramping, and explain why cramping increases during fasting and exercise.
6
3/29/2017
Utilization Stage 3: Beta Oxidation
• Four step process
• Production of – QH2
– NADH
– Acetyl CoA
Steps 1‐3 are analogous to…
7
3/29/2017
Step 1: Acyl CoA Dehydrogenase
• Similar to succinate DH from citric acid cycle
• Prosthetic FAD/FADH2
• High energy electrons passed on to QH2
• 1.5 ATP
O
R
SCoA
O
R
SCoA
Step 2: Enoyl CoA Hydratase
• Similar to fumarate
hydratase from citric acid cycle
• Addition of water
• No energy cost/production
O
R
SCoA
OH
R
O
SCoA
8
3/29/2017
Step 3: 3‐hydroxyacyl CoA DH
• Similar to malate DH from citric acid cycle
• Oxidation of secondary alcohol to ketone
• NADH production
• 2.5 ATP
OH
O
R
SCoA
O
O
R
SCoA
Step 4: Thiolase
• CoA is used as a nucleophile in a “nucleophilic acyl substitution”
• FA shortened by 2 carbons
• Acetyl CoA produced
O
O
R
SCoA
HS-CoA
O
R
O
SCoA
SCoA
9
3/29/2017
Problem 13
• The ‐Oxidation pathway was elucidated in part by Franz Knoop in 1904. He fed dogs fatty acid phenyl derivatives and then analyzed their urine for the resulting metabolites. What metabolite was produced when dogs were fed
10
3/29/2017
ATP Accounting
• How much ATP is netted from palmitate (16 carbon fatty acid)?
– Cost 2 ATP to activate to palmitate CoA
– Run through beta oxidation SEVEN times
• 7 QH2 = 10.5 ATP
• 7NADH = 17.5 ATP
– 8 acetyl CoA produced = 80 ATP
• Total: 106 ATP, or 6.625 ATP per carbon
• Compare to glucose, which is 5.33 ATP per C
Processing Other FA
• Unsaturated and trans fatty acids
– Trans is natural intermediate
– Produce 1.5 ATP less for first unsaturation, 2.5 ATP less for second unsaturation
11
3/29/2017
Processing Other FA
• Odd chain fatty acids
– Rare, but do occur in diet
– One of 2 requirements for Vitamin B12
(cobalamine) in human diet
Production of Succinate
• Carboxylase (biotin)
• Rearrangement (vitamin B12‐
radical)
• Net glucose can be produced
12
3/29/2017
Peroxisome
• Handles long fatty acids
– Chain shortening
• Branched fatty acids
• Chemistry of first oxidation is different
Alternate Fate of Acetyl CoA
• Fasting, Diabetes
– Glycolysis is down, gluconeogenesis is up
– Oxaloacetate depleted
– Citric acid cycle has diminished capacity
– Acetyl CoA levels build up
• Ketone bodies are formed
13
3/29/2017
Ketone Bodies
• Water soluble form of lipids
• Less potential energy than FA
• Main energy source of brain in starvation
• Also used in muscle and intestine
14
3/29/2017
Anabolism Overview
• Fatty acid synthesis
• Fatty acid synthesis regulation
• Cholesterol
Biosynthesis of Lipids
• Triacylglyerides as fuels
• Glycerophospholipids in membrane
• Prostaglandins as signal molecules
• Cholesterol and derivatives
15
3/29/2017
Fatty Acid Synthesis
• Opposite of beta oxidation in the sense that 2‐
carbon acetate units are linked to form even‐
chain, saturated fatty acids
• Differs from Fatty acid degradation
– In cytoplasm, not matrix
– Acyl carrier protein rather than CoA
– Enzymes linked in a complex
– Utilizes NADPH
– Energetically linked to ATP hydrolysis
Transport to Cytoplasm
NADH
NADPH
16
3/29/2017
Activation of Acetyl Group • Acetyl CoA carboxylase (analogous to pyruvate carboxylase of gluconeogenesis)
• Requires biotin, ATP
• A regulation step—shifts fuel away from CAC
17
3/29/2017
Transfer to Acyl Carrier Protein
Multifunctional Enzyme: Fatty Acid Synthase
18
3/29/2017
Four Step Elongation
• Step 1: Condensation
– Loss of CO2 drives reaction to completion
– All happens on enzyme complex
– Mechanism:
19
3/29/2017
Steps 2‐4: Opposite of beta Oxidation
• Input of 2 NADPH
• Major use of PPP
Synthesis of Palmitate
• 16‐carbon fatty acid produced in major synthesis complex
• Problem 31: What is the ATP cost of synthesizing palmitate from acetyl‐CoA?
20
3/29/2017
Regulation
• Logic of Regulation
– Acetyl CoA carboxylase
• Citrate is acetyl CoA equivalent
• Fatty Acid is feedback inhibition
– Carnitine Transporter
• Malonyl CoA
Regulation of AcetylCoA Carboxylase
• AMPK
• Citrate
• Hormone level
21
3/29/2017
Explain this graph…
Post‐synthesis Modification
• Elongations possible with other enzymes
• Many organisms can make odd‐chain fatty acids
• Essential Fatty acids
22
3/29/2017
Prostaglandins and COX Inhibitors
Cholesterol Biosynthesis
• Three Stages: Acetyl CoAIsopentyl
diphosphateSqualeneCholesterol
23
3/29/2017
Stage 1
• Similar to ketogenesis, but in cytosol
• HMG‐CoA reductase • Isoprene building block for many lipids
Stages 2 and 3
24
3/29/2017
Medical Applications
• Statins inhibit HMG‐CoA Reductase
• Problem: inhibits all steroid biosynthesis
Medical Applications
• Another strategy for lowering cholesterol is to trap bile salts in intestine so that cholesterol is diverted
25
3/29/2017
Medical Applications
• Parasites like malaria make isopentenyl
diphosphate
through a different mechanism
• A competitive inhibitor can selectively kill malaria
OH
O-
O
intermediate in
cholesterol
biosynthesis
P
-
O
O
OH
O-
O
P
-
O
OH
competitive
inhibitor
N
O
O
26